Chloride → HCID 68953351, compound

Participants

Reaction Steps

Methaneslufonyl chloride (1.52 mL, 20 mmol) is added dropwise to a mixture of (2-{(R)-2-[4-(benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-6,7-difluoroquinolin-3-yl)methanol (7.03 g, 15 mmol) and N,N-diisopropylethylamine (DIPEA, 3.41 mL, 15 mmol) in toluene (75 mL) at 0° C. The reaction mixture is stirred at ambient temperature for 1 hour. To the mixture, water and ethyl acetate are added, and the organic layer is washed with sat. NaHCO3 aq, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is dissolved with toluene and concentrated in vacuo to give crude 2-{(R)-2-[4-(benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-3-(chloromethyl)-6,7-difluoroquinoline. To a mixture of N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amine (5.88 g, 18 mmol) in DMF (60 mL) is added potassium tert-butoxide (2.03 g, 18 mmol) at 0° C., and the resulting mixture is stirred for 30 min at the same temperature. A crude 2-{(R)-2-[4-(benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-3-(chloromethyl)-6,7-difluoroquinoline dissolved in DMF (30 mL) is added dropwise to the mixture at 0° C., and the resulting mixture is stirred for 1 hour at the same temperature. Potassium tert-butoxide (1.70 g, 14 mmol) is added to the reaction mixture, and the mixture is stirred another 1 hour at room temperature. After adding water, the mixture is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate, filtrated, and concentrated. The resulting mixture is purified by silica gel column chromatography to give trans-N-(2-{(R)-2-[4-(2-benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-6,7-difluoroquinolin-3-ylmethyl)-N-[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amine as a yellow amorphous solid.

Provenance & Evidence